Showing papers by "Michael C. Neale published in 1993"
TL;DR: The results suggest that the association between smoking andMD in women is not a causal one but arises largely from familial factors, which are probably genetic, that predispose to both smoking and MD.
Abstract: • Among 1566 personally evaluated female twins from a population-based register, average lifetime daily cigarette consumption was strongly related to lifetime prevalence and to prospectively assessed 1-year prevalence of major depression (MD). Using the cotwin control method, we evaluated whether the association between smoking and lifetime MD was causal or noncausal. While the relative risk (95% confidence interval) for ever smoking given a lifetime history of MD was 1.48 (1.30 to 1.65) in the entire sample, it was 1.18 (0.88 to 1.47) and 0.98 (0.71 to 1.26), respectively, in dizygotic and monozygotic twin pairs discordant for a history of MD. The relative risk for a history of MD given ever smoking was 1.60 (1.39 to 1.83) in the entire sample, while in dizygotic and monozygotic twins discordant for smoking, it was 1.29 (0.87 to 1.74) and 0.96 (0.59 to 1.42), respectively. Controlling for personal smoking history, family history of smoking predicted risk for MD; controlling for the personal history of MD, family history of MD predicted smoking. The best-fitting bivariate twin model suggested that the relationship between lifetime smoking and lifetime MD resulted solely from genes that predispose to both conditions. These results suggest that the association between smoking and MD in women is not a causal one but arises largely from familial factors, which are probably genetic, that predispose to both smoking and MD.
812 citations
TL;DR: In women, the relationship between neuroticism and the liability to major depression is substantial and largely the result of genetic factors that predispose to both neuroticismand major depression.
Abstract: Objective: To elucidate the nature of the etiologic relationship between personality and major depression in women. Design: A longitudinal twin design in which twins completed a time 1 questionnaire and, 15 months later, were personally interviewed for the occurrence of major depression during the last year and completed a time 2 questionnaire. Both questionnaires contained short forms assessing neuroticism and extraversion. Participants: 1733 twins from female-female pairs ascertained from the population-based Virginia Twin Registry. Results: Extraversion was unrelated to lifetime or 1-year prevalence of major depression. Neuroticism was strongly related to lifetime prevalence of major depression and robustly predicted the prospective 1-year prevalence of major depression in those who, at time 1, denied previous depressive episodes. However, controlling for levels of neuroticism at time 1, levels of neuroticism at time 2 were moderately elevated in those who had had an episode of major depression between times 1 and 2 ("scar" effect) and substantially elevated in those experiencing an episode of major depression at time 2 ("state" effect). In those who developed major depression, levels of neuroticism did not predict time to onset. In the best-fit longitudinal twin model, the proportion of the observed correlation between neuroticism and the liability to major depression that is due to shared genetic risk factors was estimated at around 70%, that due to shared environmental risk factors at around 20%, and that due to a direct causal effect of major depression on neuroticism (via both "scar" and "state" effects) at around 10%. Approximately 55% of the genetic liability of major depression appeared to be shared with neuroticism, while 45% was unique to major depression. Conclusion: In women, the relationship between neuroticism and the liability to major depression is substantial and largely the result of genetic factors that predispose to both neuroticism and major depression.
648 citations
TL;DR: The model suggested that at least four major and interacting risk factor domains are needed to understand the etiology of major depression: traumatic experiences, genetic factors, temperament, and interpersonal relations.
Abstract: Objective The authors develop an exploratory, integrated etiologic model for the prediction of episodes of major depression in an epidemiologic sample of women. Method Both members of 680 female-female twin pairs of known zygosity from a population-based register were assessed three times at greater than 1-year intervals. The last two assessments included a structured interview evaluation for presence of episodes of major depression, defined by DSM-III-R, in the preceding year. The final structural equation model contained nine predictor variables: genetic factors, parental warmth, childhood parental loss, lifetime traumas, neuroticism, social support, past depressive episodes, recent difficulties, and recent stressful life events. Results The best-fitting model predicted 50.1% of the variance in the liability to major depression. The strongest predictors of this liability were, in descending order, 1) stressful life events, 2) genetic factors, 3) previous history of major depression, and 4) neuroticism. While 60% of the effect of genetic factors on the liability to major depression was direct, the remaining 40% was indirect and mediated largely by a history of prior depressive episodes, stressful life events, lifetime traumas, and neuroticism. The model suggested that at least four major and interacting risk factor domains are needed to understand the etiology of major depression: traumatic experiences, genetic factors, temperament, and interpersonal relations. Conclusions Major depression is a multifactorial disorder, and understanding its etiology will require the rigorous integration of genetic, temperamental, and environmental risk factors.
609 citations
TL;DR: A newly developed model-fitting approach which treats perceived zygosity as a form of specified familial environment is used which supports the validity of the EEA in twin studies of psychiatric disorders.
Abstract: The traditional twin method is predicated on the equal-environment assumption (EEA)--that monozygotic (MZ) and dizygotic (DZ) twins are equally correlated in their exposure to environmental events of etiologic importance for the trait under study. In 1968, Scarr proposed a test of the EEA which examines the impact of phenotypic similarity in twins of perceived versus true zygosity. We apply this test for the EEA to five common psychiatric disorders (major depression, generalized anxiety disorder, phobia, bulimia, and alcoholism), as assessed by personal interview, in 1030 female-female twin pairs from the Virginia Twin Registry with known zygosity. We use a newly developed model-fitting approach which treats perceived zygosity as a form of specified familial environment. In 158 of the 1030 pairs (15.3%), one or both twins disagreed with the project-assigned zygosity. Model fitting provided no evidence for a significant influence of perceived zygosity on twin resemblance for any of the five disorders. Although limited in power, these results support the validity of the EEA in twin studies of psychiatric disorders.
392 citations
TL;DR: Reliability of LTH of MD was modest, and was predicted by the number of depressive symptoms, treatment seeking, number of episodes, and degree of impairment, and from an "index of caseness" from these predictors, the estimated heritability was greater for more restrictive definitions.
Abstract: Background: In epidemiologie samples, the assessment of lifetime history (LTH) of major depression (MD) is not highly reliable. In female twins, we previously found that LTH of MD, as assessed at a single personal interview, was moderately heritable (approximately 40%). In that analysis, errors of measurement could not be discriminated from true environmental effects. Methods: In 1721 female twins from a populationbased register, including both members of 742 pairs, LTH of MD, covering approximately the same time period, was obtained twice, once by self-administered questionnaire and once at personal interview. Results: Reliability of LTH of MD was modest (×= + .34, tetrachoric r= + .56) and was predicted by the number of depressive symptoms, treatment seeking, number of episodes, and degree of impairment. Deriving an "index of caseness" from these predictors, the estimated heritability of LTH of MD was greater for more restrictive definitions. Incorporating error of measurement into a structural equation model including both occasions of measurement, the estimated heritability of the liability to LTH of MD increased substantially (approximately 70%). More than half of what was considered environmental effects when LTH of MD was analyzed on the basis of one assessment appeared, when two assessments were used, to reflect measurement error. Conclusions: Major depression, as assessed over the lifetime, may be a rather highly heritable disorder of moderate reliability rather than a moderately heritable disorder of high reliability.
327 citations
TL;DR: The results suggest that stressful life events reflect more than random influences, which suggest that personal and social factors that predispose to life events are substantially influenced by an individual's genetic and family background.
Abstract: Objectives: To examine the role of genetic and familialenvironmental factors in the origin of stressful life events. Design: Self-report questionnaires describing stressful life events in the last year. Participants: Both members of 2315 twin pairs ascertained from the population-based Virginia Twin Registry. Results: Life events were modestly but significantly correlated in twin pairs, and correlations in monozygotic (MZ) twins consistently exceeded those in dizygotic (DZ) twins. For total life events, the best-fitting twin model indicated that familial-environmental and genetic factors each accounted for around 20% of the total variance. Individual life events could be best divided into "network events" (directly affecting individuals in the respondent's socialnetwork) where twin resemblance was due solely to the familial environment, and "personal" events (directly affecting the response) where most twin resemblance was the result of genetic factors. Conclusions: While neither genes nor familial environment is likely to directly produce life events, personal and social factors that predispose to life events are substantially influenced by an individual's genetic and family background. These results, which suggest that stressful life events reflect more than random influences, may have important implications for our understanding of the relationship between stressful life events and psychopathology.
298 citations
TL;DR: Heritabilities were significant using a wide range of assumptions about both the base rate of homosexuality in the population and ascertainment bias and self-reported history of childhood gender nonconformity.
Abstract: • Homosexual female probands with monozygotic cotwins, dizygotic cotwins, or adoptive sisters were recruited using homophile publications. Sexual orientation of relatives was assessed either by asking relatives directly, or, when this was impossible, by asking the probands. Of the relatives whose sexual orientation could be confidently rated, 34 (48%) of 71 monozygotic cotwins, six (16%) of 37 dizygotic cotwins, and two (6%) of 35 adoptive sisters were homosexual. Probands also reported 10(14%) nontwin biologic sisters to be homosexual, although those sisters were not contacted to confirm their orientations. Heritabilities were significant using a wide range of assumptions about both the base rate of homosexuality in the population and ascertainment bias. The likelihood that a monozygotic cotwin would also be homosexual was unrelated to measured characteristics of the proband such as self-reported history of childhood gender nonconformity. Concordant monozygotic twins reported similar levels of childhood gender nonconformity.
255 citations
TL;DR: Comorbidity between MD and alcoholism in women is substantial and appears to result largely from genetic factors that influence the risk to both disorders, but common environmental risk factors also contribute.
Abstract: Background: Although major depression (MD) and alcoholism co-occur in clinical and epidemiologic samples of women more often than expected by chance, the magnitude and causes of this comorbidity are uncertain. Methods: Personal interviews were conducted with 2163 female twins from a population-based twin registry. Bivariate twin analysis was performed using two definitions of MD and three definitions of alcoholism of varying diagnostic breadth. Results: Odds ratios ranged from 2.7 to 6.0 and were consistently higher using narrower diagnostic criteria for either disorder. Twin analyses found (1) no evidence for familial environmental factors for either MD or alcoholism; (2) significant genetic correlations, ranging from +.4 to +.6, between MD and alcoholism, which were higher using narrower criteria for alcoholism; (3) significant in- dividual-specific environmental correlations, ranging from +.2 to +.4, for all but one of the diagnostic combinations, which were higher using narrower criteria for MD. Conclusions: Comorbidity between MD and alcoholism in women is substantial and appears to result largely from genetic factors that influence the risk to both disorders, but common environmental risk factors also contribute. However, genetic factors exist that influence the liability to MD without influencing the risk for alcoholism and vice versa. Narrowing the diagnostic criteria for MD or alcoholism increases comorbidity, but for different reasons narrow diagnostic criteria for MD increase the environmental sources of comorbidity while narrow diagnostic criteria for alcoholism increase the genetic sources of comorbidity.
246 citations
TL;DR: Cross-sectional family data may prove useful in cases where conventional methods to establish causality, by intervention, by prospective study, or by measurement of instrumental variables, are infeasible economically, ethically or practically.
Abstract: We review the conditions under which cross-sectional family data (e.g., data on twin pairs or adoptees and their adoptive and biological relatives) are informative about direction of causation. When two correlated traits have rather different modes of inheritance (e.g., family resemblance is determined largely by family background for one trait and by genetic factors for the other trait), cross-sectional family data will allow tests of strong unidirectional causal hypotheses (A and B are correlated “because of the causal influence of A on B” versus “because of the causal influence of B on A”) and, under some conditions, also of the hypothesis of reciprocal causation. Possible sources of errors of inference are considered. Power analyses are reported which suggest that multiple indicator variables will be needed to ensure adequate power of rejecting false models in the presence of realistic levels of measurement error. These methods may prove useful in cases where conventional methods to establish causality, by intervention, by prospective study, or by measurement of instrumental variables, are infeasible economically, ethically or practically.
201 citations
TL;DR: It is suggested that in the general population panic disorder is only a moderately heritable condition, which is at variance with results from several previous investigations based on clinically ascertained samples.
Abstract: Previous studies based on probands from clinical samples suggest that panic disorder aggregates strongly in families and may be due to a highly penetrant single major locus. In this study we examine panic disorder as assessed at blind, structured psychiatric interview in 2163 women from a population-based twin registry. DSM-III-R diagnoses were assigned at a narrow and at a broad level both by clinician review and by computer algorithm. The familial aggregation of panic disorder in this sample was only modest. The relatively small number of affected individuals prevented a definitive resolution of competing genetic and non-genetic models of familial transmission. Although there was some inconsistency across diagnostic approaches, most results suggested that the familial aggregation of panic disorder was due largely to genetic factors. Using a multifactorial-threshold model, the best estimates of the heritability of liability ranged from 30 to 40%. From a familial perspective, panic disorder with phobic avoidance appears to represent a more severe form of the syndrome than panic disorder without avoidance. Our results, which suggest that in the general population panic disorder is only a moderately heritable condition, are at variance with results from several previous investigations based on clinically ascertained samples.
172 citations
TL;DR: Comparing the probandwise concordance rate (PRC) for affective illness (AI) in monozygotic and dizygotic twins in samples ascertained through psychiatric hospitalization vs samples from the general population found genetic factors play a major role in the etiology of AI in Sweden.
Abstract: Objective: We sought to compare the probandwise concordance rate (PRC) for affective illness (AI) in monozygotic (MZ) and dizygotic (DZ) twins in samples ascertained through psychiatric hospitalization vs samples from the general population. Methods: Twins were ascertained through psychiatric hospitalization for AI from the Swedish Psychiatric Twin Registry or as a matched sample from the population-based Swedish Twin Registry. Lifetime diagnoses were based on a mailed questionnaire containing, in self-report format, DSM-III-R criteria for mania and major depression. Returned questionnaires were obtained from 1484 individuals and both members of 486 pairs, of whom 154 were classified as MZ, 326 as DZ, and six of unknown zygosity. Results: No evidence was found for violations of the equal environment assumption. Using either a narrow or broad diagnostic approach, the risk for AI in cotwins of proband twins was independent of the gender, polarity (ie, unipolar vs bipolar) and mode of ascertainment of the affected proband (ie, via hospitalization vs from the general population). Combining both subsamples, PRC for total AI using narrow diagnostic criteria was 48.2% in MZ and 23.4% in DZ twins. Using broad diagnostic criteria, the parallel figures were 69.7% and 34.9%. The risk for bipolar illness was substantially increased in the cotwins of probands with bipolar AI. Conclusions:
TL;DR: Self-report data on smoking initiation (whether the respondent admitted ever having smoked) were obtained from three large adult twin samples and found no evidence for cohort differences in genetic and environmental effects (no Genotype x Cohort interaction).
TL;DR: Bivariate twin analyses to decompose the genetic and environmental sources of comorbidity between major depression and the phobias suggest that a modest proportion of the genetic vulnerability to MD also influences the risk for all phobic subtypes, with the possible exception of situational phobia.
Abstract: In a population based sample of 2163 personally interviewed female twins, substantial comorbidity was observed between DSM-III-R defined major depression (MD) and 4 subtypes of phobia: agoraphobia, social phobia, animal phobia and situational phobia. However, the level of comorbidity of MD with agoraphobia was much greater than that found with the other phobic subtypes. We conducted bivariate twin analyses to decompose the genetic and environmental sources of comorbidity between MD and the phobias. Our results suggest that a modest proportion of the genetic vulnerability to MD also influences the risk for all phobic subtypes, with the possible exception of situational phobias. Furthermore, the magnitude of comorbidity resulting from this shared genetic vulnerability is similar across the phobic subtypes. By contrast, the non-familial environmental experiences which predispose to depression substantially increase the vulnerability to agoraphobia, have a modest impact on the risk for social and situational phobias and no effect on the risk for animal phobias. The increased comorbidity between MD and agoraphobia results, nearly entirely, from individual-specific environmental risk factors for MD which also increase the risk for agoraphobia but not for other phobias.
TL;DR: Two “four-class” models for etiological heterogeneity which make different assumptions about the way in which genes and environment interact to produce complex disease phenotypes are explored.
Abstract: A model based on the latent class model is developed for the effects of genes and environment on multivariate categorical data in twins. The model captures many essential features of dimensional and categorical conceptions of complex behavioral phenotypes and can include, as special cases, a variety of major locus models including those that allow for etiological heterogeneity, differential sensitivity of latent classes to measured covariates, and genotype × environment interaction (G×E). Many features of the model are illustrated by an application to ratings on eight items relating to conduct disorder selected from the Rutter Parent Questionnaire (RPQ). Mothers rated their 8-to 16-year-old male twin offspring [174 monozygotic (MZ) and 164 dizygotic (DZ) pairs]. The impact of age on the frequency of reported symptoms was relatively slight. Preliminary latent class analysis suggests that four classes are required to explain the reported behavioral profiles of the individual twins. A more detailed analysis of the pairwise response profiles reveals a significant association between twins for membership of latent classes and that the association is greater in MZ than DZ twins, suggesting that genetic factors played a significant role in class membership. Further analysis shows that the frequencies of MZ pairs discordant for membership of some latent classes are close to zero, while others are definitely not zero. One possible explanation of this finding is that the items reflect underlying etiological heterogeneity, with some response profiles reflecting genetic categories and others revealing a latent environmental risk factor. We explore two “four-class” models for etiological heterogeneity which make different assumptions about the way in which genes and environment interact to produce complex disease phenotypes. The first model allows for genetic heterogeneity that is expressed only in individuals exposed to a high-risk (“predisposing”) environment. The second model allows the environment to differentiate two forms of the disorder in individuals of high genetic risk. The first model fits better than the second, but neither fits as well as the general model for four latent classes associated in twins. The results suggest that a single-locus/two-allele model cannot fit the data on these eight items even when we allow for etiological heterogeneity. The pattern of endorsement probabilities associated with each of the four classes precludes a simple “unidimensional” model for the latent process underlying variation in symptom profile in this population. The extension of the approach to larger pedigrees and to linkage analysis is briefly considered.
TL;DR: It is suggested that genetic factors play a moderate etiologic role in the 1YP-MD, the temporal stability of the liability to major depression in adult women is largely or entirely genetic in origin, and environmental Factors play a significant role inThe etiology of major depression, but their effects are generally transitory and do not result in enduring changes in the liabilities to illness.
Abstract: Objectives: This study seeks to clarify the etiologic importance and temporal stability of the genetic and environmental risk factors for 1-year prevalence of major depression (1YP-MD) in women. Design: One-year prevalence of major depression was personally assessed, using DSM-III-R criteria, at two time points a minimum of 1 year apart. Participants: Both members of 938 adult femalefemale twin pairs ascertained from the population-based Virginia Twin Registry. Results: The correlation in liability to 1YP-MD was much greater in monozygotic (MZ) than in dizygotic (DZ) twins at time 1 alone, time 2 alone, or at either time 1 or time 2. Model fitting suggested that the liability to 1YP-MD was due to additive genes and individual specific envi- ronment with a heritability of 41% to 46% and was not biased by violations of the equal environment assumption. Jointly analyzing both times of assessment using a longitudinal twin model suggested that, over a 1-year period, genetic effects on the liability to 1YP-MD were entirely stable, while environmental effects were entirely occasion specific. Conclusions: These results suggest that (1) genetic factors play a moderate etiologic role in the 1YP-MD, (2) the temporal stability of the liability to major depression in adult women is largely or entirely genetic in origin, and (3) environmental factors play a significant role in the etiology of major depression, but their effects are generally transitory and do not result in enduring changes in the liability to illness.
TL;DR: Likelihood formulae are presented that permit quantification and significance testing of volunteer bias and some methods of reducing the computational burden of multidimensional integration to allow extension to multivariate data are described.
Abstract: If pairs of relatives correlate in their liability to participate in a research project, it is possible to test for the effects of volunteering on the criterion variable of interest. Much of the information for this test comes from a difference in criterion variable mean between individuals with and those without a cooperative relative. Also, if data are available from more than one class of relative, it may be possible to discriminate between (i) volunteering that occurs as a consequence of the criterion variable and (ii) volunteering as a cause of the criterion. Likelihood formulae are presented that permit quantification and significance testing of volunteer bias. If data are collected from a genetically informative design such as a twin study, it is possible to estimate genetic and environmental parameters independent of the contaminating effects of such bias. We describe some methods of reducing the computational burden of multidimensional integration to allow extension to multivariate data. Implications for research design and management are discussed.
TL;DR: A simple biometric model specifying only age-specific genetic additive effects and environmental effects fitted well to correlations between cotwins, pairs of siblings, and parent-offspring dyads in subsets of relatives grouped by age differences.
Abstract: Correlations between relatives were determined for systolic and diastolic blood pressure. The correlations decrease as age differences between relatives increase in a Norwegian sample with 43,751 parent-offspring pairs, 19,140 pairs of siblings, and 169 pairs of twins. A simple biometric model specifying only age-specific genetic additive effects and environmental effects fitted well to correlations between cotwins, pairs of siblings, and parent-offspring dyads in subsets of relatives grouped by age differences. None of the environmental effects appeared to be due to environmental factors that are shared by family members. Models that excluded a parameter for the age-specific genetic influence did not fit the data. The results may partly explain what seems to be a discrepancy between relatively low parent-offspring correlations from previous nuclear family studies and high correlations from twin studies, especially in identical twins.
01 Jan 1993
TL;DR: This study compared 54 purging bulimics with 69 nonpurging Bulimics ascertained from a population-based register of Virginia female twins to see if such a division is justified.
Abstract: There has been recent interest in the possibility of dividing bulimia nervosa into two subtypes based on the method of weight prevention utilized by the individual. In an attempt to see if such a division is justified, this study compared 54 purging bulimics with 69 nonpurging bulimics ascertained from a population-based register of Virginia female twins. A bulimic was defined as a "purger" if she engaged in vomiting or laxative abuse. These two groups were examined on a variety of demographic, weight, and personality measures after controlling for the presence of obesity. No significant differences were found between the two groups on any of the variables examined.
TL;DR: During the course of a survey of fragile site expression in lymphocytes from twins one member of a dizygotic pair was found to be mosaic for trisomy 8, and metaphases from this individual were analyzed.
Abstract: During the course of a survey of fragile site expression in lymphocytes from twins one member of a dizygotic pair was found to be mosaic for trisomy 8. One hundred fifty metaphases from this individual were analyzed (100 treated with aphidicolin and 50 untreated); 43% were 46,XY and 57% 46,XY, +8. No differences were observed between the treated and control cultures in either the proportions of normal and trisomic metaphases or the overall or specific fragile site expression in the normal and trisomic cells. © 1993 Wiley-Liss, Inc.